1. Field of Invention
The present invention relates to polymorphs of the 3-pyrrole substituted 2-indolinone compound 5-(5-fluoro-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-pyrrolidin-1-yl-ethyl)-amide.
2. State of the Art
5-(5-fluoro-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-pyrrolidin-1-yl-ethyl)-amide is a compound that exhibits protein kinase (PK) modulating ability. The compound is therefore useful in treating disorders related to abnormal PK activity.
Briefly, PKs are enzymes that catalyze the phosphorylation of hydroxy groups on tyrosine, serine and threonine residues of proteins. The consequences of this seemingly simple activity are staggering, since virtually all aspects of cell life (e.g., cell growth, differentiation and proliferation) and, in one way or another, depend on PK activity. Furthermore, abnormal PK activity has been related to a host of disorders, ranging from relatively non-life threatening diseases such as psoriasis to extremely virulent diseases such as glioblastoma (brain cancer).
5-[5-fluoro-2-oxo-1,2-dihydroindol-(3Z)-ylidenmethyl]-2,4-dimethyl- 1H-pyrrole-3-carboxylic acid (2-pyrrolidin-1-ylethyl)-amide is an inhibitor of receptor tyrosine kinases (RTKs); a class of PK. The RTKs and their ligands, VEGF, PDGF, and FGF mediate neo-vascularization, known as angiogenesis, in solid tumors. Consequently, by inhibiting the RTKs, the growth of new blood vessels into tumors may be inhibited. Theoretically, this new class of molecules, termed antiangiogenesis agents, have much less toxicity to the body compared to conventional anti-cancer drugs. 5-[5-fluoro-2-oxo-1,2-dihydroindol-(3Z)-ylidenmethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-pyrrolidin-1-ylethyl)-amide is currently being developed for treating cancers in companion animals, mainly dogs and is also useful for the treatment of, inter alia, cancer in humans. Such cancers include, but are not limited to leukemia, brain cancer, non-small cell lung cancer, squamous cell carcinoma, astrocytoma, Kaposi's sarcoma, glioblastoma, lung cancer, bladder cancer, head and neck cancer, melanoma, ovarian cancer, prostate cancer, breast cancer, small-cell lung cancer, glioma, colorectal cancer, genitourinary cancer and gastrointestinal stromal cancer. Also, overexpression of mast cells, including, but not limited to, mastocyctosis is contemplated.